tbuckley/cabot-search huggingface dataset:
Abstract PD6-10: PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies
Authors: Philip A. Haddad, Usman Zaheer
Journal: Cancer Research (2023)

Abstract Background/Rationale: Male breast cancer accounts for less than 1 percent of all cancer diagnoses in men. Because it is rare, it does not lend itself to large, randomized trials. In general, the approach to the treatment of early, non-metastatic male breast cancer has largely been extrapolated from female breast cancer trials. Specifically, the data on early-stage post mastectomy radiation therapy (PMRT) is limited, and its benefits remain unclear. Objectives: We conducted this meta-analysis to determine the impact of PMRT on clinical outcomes of men with breast cancer. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language, diagnosis of invasive non-metastatic male breast cancer (MBC), comparative studies of PMRT versus none, and studies that reported the incidence of local and distant recurrences as well as survival data in the compared arms. A meta-analysis using the Mantel-Haenszel method for calculating the weighted pooled relative risk (RR) under the fixed effects model. Subsequently, the heterogeneity statistic gets incorporated to calculate the summary RR under the random effects model. Results: Ten retrospective comparative studies with 3912 patients were included and analyzed. Eight studies reported survival data. Six and three studies reported local and distant recurrence incidence, respectively. PMRT did not have an impact on overall survival or distant recurrences. However, PMRT significantly lowered the RR of locoregional recurrences (RR=0.53, 95%CI 0.31-0.92). In addition, when survival was analyzed by TNM stage and N status, PMRT was found to have a significant reduction in RR of death in stage III (RR=0.85, 95%CI 0.75-0.97), N1 (RR=0.77, 95%CI 0.61-0.98), and N2 (RR=0.61, 95%CI 0.49-0.78) disease. Conclusions: This is the first meta-analysis to show that PMRT is associated with a lower relative risk of death in stage III MBC as well as N1 and N2 disease. It also demonstrates a significant reduction in RR of locoregional recurrences. In the absence of randomized clinical trials, it represents the most compelling data supporting the use of PMRT in this MBC patient population. Citation Format: Philip A. Haddad, Usman Zaheer. PD6-10 The impact of post mastectomy radiation therapy on clinical outcomes of male breast cancer: A meta-analysis of comparative studies [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD6-10.
Abstract WS2-1: Drug-tolerant persister cells in cancer
Authors: Joan Brugge
Journal: Cancer Research (2023)

Abstract Despite favorable initial response to therapy, many cancer patients develop recurrent disease and succumb to it within five years of diagnosis. While there has been much progress in characterizing the pathways that contribute to stable genetic drug resistance, non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer. In my presentation, I will discuss different types of non-genetic, reversible mechanisms that confer therapy resistance, those involving immediate adaptive responses to stresses associated with therapies, and the other states associated with longer term persistence. I will include a discussion of strategies to target the vulnerabilities associated with each of these adaptive responses. Citation Format: Joan Brugge. Drug-tolerant persister cells in cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-1.
Abstract WS1-2: How to measure and improve drug adherence in clinical trials
Authors: Dawn Hershman
Journal: Cancer Research (2023)

Abstract The past decade has seen a dramatic increase in the number of Food and Drug Administration approval of oral anti-cancer drugs (OACDs). In 2018 alone, OACDs comprised ten of the sixteen newly approved oncology therapeutics in the United States. Despite the clinical benefits and convenience of OACDs, these new oral options present potential challenges, including polypharmacy, and can result in increased toxicities, drug–drug interactions (DDIs), inappropriate consumption of medications, and medication non-adherence. Adverse drug events have the potential to affect quality of life, healthcare utilization, treatment response, and survival. For the treatment of breast cancer, Endocrine therapies have remained a critical component of care for early stage and advance disease. Despite the proven efficacy adherence to therapy is suboptimal. Issues related to non-adherence are increasingly important, as analyses from prospective randomized trials show compliance to endocrine therapy is associated with improved disease-free survival. The reasons for non-adherence to hormonal therapy are multifactorial. Barriers to compliance include patient, physician, medication and system related variables and poor compliance is usually associated with a combination of these factors. Characteristics associated with non-adherence include very high and low age, minority race, being single, increased number of comorbidities, lack of knowledge about efficacy of AI therapy, history of non-adherence to other chronic medications, limited insurance status, and higher out of pocket costs. Side effects from hormonal therapy is the most common reason for early discontinuation. An understanding of factors that contribute to non-adherence and interventions that have been tested to improve adherence will be discussed. Medication compliance has become a more salient issue in cancer care with the increased availability of oral antineoplastic therapies for breast cancer. The treatment of BC now routinely encompasses targeted therapies such as oral poly(ADP-ribose) polymerase (PARP) inhibitors and cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors, PI3 Kinase(Pi3K) Inhibitors, in addition to traditional ET. Furthermore, as advances in BC treatment have improved long-term prognosis, the management of other chronic conditions has become an essential component of BC survivorship care. It remains unclear how this increased oral medication burden on BC survivors affects compliance with both ET and other chronic medications. Issues related to adherence measurement will be discussed. Citation Format: Dawn Hershman. How to measure and improve drug adherence in clinical trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS1-2.
Abstract WS2-4: Clinical implications of tumor heterogeneity single cell genomics
Authors: Nnennaya Kanu
Journal: Cancer Research (2023)

Abstract An understanding of how and why somatic mutations accumulate is required to shed light on cancer evolution. DNA replication during each cell cycle is an essential and highly regulated process that ensures the correct duplication of the entire genome. The timing of DNA replication has been indirectly linked to mutation acquisition and genome instability. However, the extent and the importance of altered replication timing (ART) from normal to cancer cells, and whether this process directly influences mutation acquisition during cancer evolution, have not been explored. Here we evaluated the impact of ART by analysing data from 1271 whole-genome sequenced lung (100,000 Genomes Project 1) and breast (560 breast cancer genomes from Nik-Zainal et al. 2) tumours, together with replication-timing sequencing data of multiple cancer and normal cell lines. We find that 6%-18% of the genome is subject to ART in cancer cells. Genomic regions subject to a shift from early to late replication in cancer cells exhibit an increased mutation rate in tumours and are associated with distinct mutational signatures compared to unaltered early replicated regions. In particular, we identify APOBEC3-mediated mutation clusters (omikli events) in unaltered early and late-to-early ART regions, associated with the acquisition of driver mutations. We demonstrate that ART is a relatively early event during the evolution of breast cancer and lung adenocarcinomas. Finally, genes replicated early in cancer but late in normal cells exhibit an up-regulated expression in tumour samples. The incorporation of single-cell DNA sequencing further enables accurate identification of proliferation rates. Taken together, replication timing alterations during malignant transformation are prevalent in cancer and significantly impact the genomic and transcriptomic landscape during tumour evolution. Citation Format: Nnennaya Kanu. Clinical implications of tumor heterogeneity single cell genomics [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-4.
Abstract P6-01-13: Identification of Protein Biomarkers for Early Detection and Stratification of Triple Negative Breast Cancer
Authors: Essraa metwali, Stephen Pennington
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) is the most frequent malignancy in women worldwide. Breast cancer affects roughly 3,000,000 people worldwide, with triple negative breast cancer (TNBC) accounting for 10-15% of all cases. In comparison to other types of breast cancer, TNBC stands out for its heterogenies disease, poor prognosis and aggressive behaviour. In the early stages of TNBC, neoadjuvant chemotherapy (NAC), which is given to the patient before surgery, has been considered a viable treatment strategy. Pathological complete response (pCR), which has been shown to increase estimates of disease-free (the amount of time following treatment during which there are no signs of malignancy), distant recurrence-free (the cancer has spread to far-off regions of the body) and overall survival, has been linked to NAC in 30% of patients. The objective of this study was to apply mass-spectrometry-based proteomics to serum samples from TNBC patients who have received NAC to identify i) biomarkers that might predict response to NAC, ii) biomarkers that might correlate with the extent of residual disease. These biomarkers will potentially inform treatment decisions such as the escalation/de-escalation of chemotherapy dosage for early TNBC patients. In this study, two proteomic approaches have been used to identify and measure protein candidate biomarkers: un-biased LC-MS/MS and targeted proteomics respectively. The discovery approach led to the identification of 17 unique proteins and 118 unique peptides that were differently expressed. The developing of a multiple reaction monitoring (MRM) assay for biomarker evaluation will be based on the prioritization of the potential signature proteins and other proteins obtained from public resources. Subject to successful evaluation and subsequent validation the candidate biomarkers may be beneficial for identifying TNBC patients who will achieve residual disease after NAC. Citation Format: Essraa metwali, Stephen Pennington. Identification of Protein Biomarkers for Early Detection and Stratification of Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-13.
Abstract P3-07-17: Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity
Authors: Lifang Yang, Anthony Nanajian, Stephen Beebe, Siqi Guo
Journal: Cancer Research (2023)

Abstract Cancer immunotherapy has had a significant impact on the management of many types of solid tumors. While some patients respond favorably to it, a significant number of patients do not respond or initially respond but develop resistance later, highlighting an unmet need to improve the effectiveness of this treatment. Cancers with intrinsic resistance include breast cancer, not only respond poorly to single agent immunotherapy, but also often show no durable response. Tumor microenvironment (TME) plays a critical role in both pre-existing and acquired immune resistance which is responsible for the low immunogenicity of cancers. We previously reported that an electrical engineering technology generating nanosecond length electric pulses (nsEP) can greatly enhance the immunogenicity of poorly immunogenic cancers including 4T1 breast and Pan02 pancreatic in animal models. To understand how nsEPs overcome predominant immunosuppression in the TME to induce a strong immune response, we further investigated the effects of nsEPs on the breast TME by performing transcriptomic and immune profiling of 4T1 breast cancer cells treated with nsEP. RNAseq data and cell death signaling results demonstrated that nsEPs induced regulated necrotic cell death rather than apoptosis. NsEPs-treated cancer cells greatly decreased angiogenic factors and multiple chemoattracts for myeloid-derived suppressor cells (MDSCs) and macrophages. On the other hand, nsEP-treated cancer cells significantly upregulated chemoattracts for T lymphocytes and a number of proinflammatory/immunostimulatory cytokines. Flow cytometry analysis showed that the dynamic changes of TME following nsEP treatment included: (1) the significant reduction of immunosuppressive cells (MDSCs, Tregs and TAMs); (2) the preservation of cytotoxic CD8+ T cells and conventional CD4+ T cells; and (3) a persistent elevation in cytotoxic cells vs Treg ratio and tissue resident memory CD8+ T cells. Taken together, our results suggest nsEP is a TME modifier that can potentially overturn the immunosuppressive hurdle in the TME to promote antitumor immunity. Citation Format: Lifang Yang, Anthony Nanajian, Stephen Beebe, Siqi Guo. Nanosecond Electric Pulses Modify Breast Tumor Microenvironment to Promote Antitumor Immunity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-17.
Abstract P6-01-12: Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery
Authors: Yidan Zhu
Journal: Cancer Research (2023)

Abstract Abstract Background Previous studies of immune-related gene signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery. Methods We applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared. Results We observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher gene expression scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P &amp;lt; 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR+) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors. Conclusions IGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2+ cases. Citation Format: Yidan Zhu. Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-12.
Abstract P6-01-03: Tumor-infiltrating lymphocytes (TILs) and 21-gene recurrence score in 1,883 patients with ER+/HER2- breast cancer
Authors: Sung Gwe Ahn, Ji Soo Jang, Yoonwon Kook, Seung Ho Baek, Sae Byul Lee, Soong June Bae, Joon Jeong
Journal: Cancer Research (2023)

Abstract Background: In ER+/HER2- breast cancer, several lines of evidence suggest that tumors with high level of tumor-infiltrating lymphocytes (TILs) have a greater chance of obtaining a pathological complete response (pCR) after neoadjuvant chemotherapy. In addition, high 21-gene recurrence score (RS) is associated with an increasing rate of pCR in luminal tumors. We investigated the relationship between TIL and RS in 1,883 patients with early ER+HER2- breast cancer. Method: In 1,883 ER+ breast cancer patients with 21-gene assay, TIL level was evaluated. Correlation between continuous TIL and RS was investigated. Logistic-regression analysis was performed to identify risk factors for high RS (26). The cut-off for high TIL was 50%. Recurrence-free survival (RFS) was investigated. Results: A weak positive correlation between TIL level and RS was observed (correlation coefficient=0.283, p&amp;lt; 0.001) in all patients. Average TIL level of the high RS tumors was significantly higher. Two parameters were positively correlated in both two groups classified by age 50 years (correlation coefficient=0.281 in the age 50; correlation coefficient=0.288 in the age&amp;gt;50). Either continuous TILs or binary high TIL level was demonstrated to be an independent factor for high RS. When all patients were divided into 4 groups using TIL and RS (low-RS/low-TIL, low-RS/high-TIL, high-RS/low-TIL, and high-RS/high-TIL), the RFS was worst in the low-TIL/high-RS group (p&amp;lt; 0.001). Conclusions: Our findings show that TIL level is correlated with RS in ER+ breast cancer regardless of age and suggest that high TIL level can be regarded as a risk factor for high RS. Multigene assay could be integrated in designing clinical trials evaluating immune-check point blockades in luminal breast cancer. Recurrence-free survival according to RS and TIL Table 1. 5-years RFS according to TIL and RS Citation Format: Sung Gwe Ahn, Ji Soo Jang, Yoonwon Kook, Seung Ho Baek, Sae Byul Lee, Soong June Bae, Joon Jeong. Tumor-infiltrating lymphocytes (TILs) and 21-gene recurrence score in 1,883 patients with ER+/HER2- breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-03.
Abstract P6-10-18: Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer
Authors: Metin Cetin, Ozge Saatci, Ozge Akbulut, Chad Beneker, Abdol-Hossein Rezaeian, Mikhail Chernov, Campbell McInnes, Ozgur Sahin
Journal: Cancer Research (2023)

Abstract Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of all breast cancer patients yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily with conventional chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the benefit of current therapeutic strategies used in chemoresistant TNBC, i.e., immunotherapy and antibody-drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is an urgent need to identify novel and effective treatment strategies to overcome chemoresistance. Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX), a member of LOX family, as a key mediator of chemoresistance in TNBC. However, currently available LOX inhibitors are either non-selective and/or show toxicity. Here, we performed a high-throughput cell-based LOX activity screen (HTS) with more than 5,000 molecules selected from a diversified compound library and identified the bi-thiazole derivatives as novel potent LOX inhibitors. Our structure activity relationship (SAR) analysis resulted in two lead compounds 6403, a relatively LOX-specific inhibitor, and 6415, a more LOX/LOXL2 inhibitor. Both compounds reduced collagen cross-linking (canonical function of LOX) and led to chemosensitization in TNBC cell lines and in chemoresistant TNBC PDX organoids. In addition, 6403 and 6415 reduced the TGF-beta induced fibrosis and inhibited migration capacity of the breast cancer cell lines. Importantly, 6403 showed excellent pharmacokinetic profile and did not lead to any observable toxicity in mice. Notably, 6403 overcame doxorubicin resistance in LOX-expressing 4T1 syngeneic model with no apparent toxicity. Furthermore, our novel LOX and LOX/LOXL2 dual inhibitors show superior inhibition of LOX activity compared to the recently developed and clinically tested LOX family or LOXL2/LOXL3 inhibitors. Overall, we identified novel potent LOX inhibitors with no observable toxicity for further preclinical development and future clinical testing to overcome chemoresistance in TNBC. Citation Format: Metin Cetin, Ozge Saatci, Ozge Akbulut, Chad Beneker, Abdol-Hossein Rezaeian, Mikhail Chernov, Campbell McInnes, Ozgur Sahin. Developing novel lysyl oxidase (LOX) inhibitors to overcome chemotherapy resistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-18.
A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19
Authors: Lin Xia, Lun-zhi Yuan, Ya-hong Hu, Jun-yi Liu, Guo-sheng Hu, Ruo-yao Qi, Tian-ying Zhang, Hua-long Xiong, Zao-zao Zheng, Hong-wei Lin, Jia-mo Zhang, Chao Yu, Ming Zhou, Jian Ma, Tong Cheng, Ri-rong Chen, Yi Guan, Ning-shao Xia, Wen Liu
Journal: Cellular and Molecular Immunology (2023)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this “two-cell” (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.